Trileptal Clinical Protocols

<table bordercolor="#c0c0c0" cellspacing="1" cellpadding="7" width="672" border="1"> <tbody> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <br /> <br /> <p> <b><font face="Times" size="5">Trileptal Clinical Protocols</font></b> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times" size="1">The Trileptal NDA was supported by six studies: four monotherapy trials that included adults and children and two adjunctive therapy trials, one in adults and one in children.</font></i></b> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times">Protocol 004</font></i></b> </p> </td> </tr> <tr> <td valign="top" width="21%"> </td> <td valign="top" width="79%"> <p> <font face="Helvetica Condensed" size="2">The double-blind, parallel-group trial enrolled 102 patients aged 11-62. The trial's primary objective was to evaluate safety and efficacy of oxcarbazepine (OXC) monotherapy versus placebo in patients with refractory partial-onset seizures, with or without secondarily generalized seizures, who had completed a pre-surgical evaluation. The primary outcome measure was time to exit criteria.<br /> <br /> Patients that had between two and 11 seizures in 48 hours were randomized to placebo or OXC (1500 mg/day on the first day, followed by 2400 mg/day) for nine days, or until one of three exit criteria occurred. Exit criteria were occurrence of a fourth partial seizure; two new-onset generalized tonic-clonic seizures, if none had occurred during the previous year; or serial seizures or status epilepticus.<br /> <br /> Results were statistically significant in favor of Trileptal for time to exit criteria (p=0.0001). The ten-day treatment period was completed by 27 patients in the OXC group vs. six patients in the placebo group, and 21 patients in the OXC group met at least one of the exit criteria compared to 43 in the placebo group.</font> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times">Protocol 025</font></i></b> </p> </td> </tr> <tr> <td valign="top" width="21%"> </td> <td valign="top" width="79%"> <p> <font face="Helvetica Condensed" size="2">The double-blind, parallel-group study randomized 67 patients ages 8-69 to OXC (32 patients) or placebo (35 patients) following a 56-day baseline period, during which patients had to experience at least two seizures per month. Patients could not have received AED treatment 90 days prior to randomization. OXC treatment was initiated at 300 mg b.i.d. and titrated over a seven-day period to 600 mg b.i.d., followed by maintenance treatment for 84 days. After completion of the maintenance phase, study participants were eligible to enter an open, uncontrolled extension phase.<br /> <br /> The primary outcome of the study was time to first partial seizure. Median time to first partial seizure was 11.7 days in the OXC group versus 3.2 days for placebo patients (p=0.046).</font> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times">Protocol 026</font></i></b> </p> </td> </tr> <tr> <td valign="top" width="21%"> </td> <td valign="top" width="79%"> <p> <font face="Helvetica Condensed" size="2">The double-blind, parallel-group trial enrolled 143 patients to evaluate high-dose versus low-dose Trileptal in participants with uncontrolled partial onset seizures. Patients had previously been taking carbamazepine monotherapy at doses of 800 to 1600 mg/day and were considered refractory to carbamazepine. The study was divided into five separate phases: screening, open-label conversion, open-label baseline, double-blind treatment and open-label long-term extension.<br /> <br /> During the 56-day screening phase, patients on carbamazepine who had a seizure frequency of two to 40 seizures per month were enrolled. In the 28-day, open-label conversion phase, patients were evaluated for trial eligibility and were titrated to OXC. Patients were maintained on 1200 mg b.i.d. OXC during the 62-day open-label baseline phase. Following open-label treatment, 96 patients were randomized to a double-blind phase and received one of two doses of OXC: 300 mg/day (45 patients) or 2400 mg/day (51 patients).<br /> <br /> Patients that met any of four exit criteria were considered to have completed the study and were permitted to enter the open-label extension phase. The exit criteria were: a two-fold increase from baseline in the number of seizures; a two-fold increase in the highest consecutive two-day seizure frequency that occurred during baseline; occurrence of a single generalized seizure if none occurred during baseline; or a prolonged generalized seizure.<br /> <br /> Thirty of the 2400 mg/day patients met the exit criteria, compared to 40 of the 300 mg/day group. The exit-rate data was statistically significant in favor of the high-dose Trileptal group (p=0.0001).</font> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times">Protocol 028</font></i></b> </p> </td> </tr> <tr> <td valign="top" width="21%"> </td> <td valign="top" width="79%"> <p> <font face="Helvetica Condensed" size="2">The double-blind, parallel-group study compared safety and efficacy of high-dose (2400 mg/day) and low-dose OXC (300 mg/day). The study, which enrolled patients ages 11-66 who were receiving one or two AEDs, was divided into three phases: baseline, double-blind and open-label extension. After a 56-day baseline period, 87 patients were randomized to either high- or low-dose OXC (41 and 46 patients, respectively). Patients were titrated over 15 days to the high dose. Secondary AEDs were discontinued on the first day, and primary AEDs were withdrawn by day 43 of the 126-day double-blind treatment phase.<br /> <br /> Patients either completed the entire study or met one of the four exit criteria described in protocol 026. Study results were statistically significant for the 2400 mg group: 14 high-dose patients met the exit criteria as compared to 42 of the 300 mg group (p&lt;0.0001).</font> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times">Protocol OT/PE1</font></i></b> </p> </td> </tr> <tr> <td valign="top" width="21%"> </td> <td valign="top" width="79%"> <p> <font face="Helvetica Condensed" size="2">This adjunctive study was a double-blind, parallel-group trial in which 692 patients, ages 15-66, received up to three concomitant AEDs and were randomized to receive either placebo or OXC 600 mg/day, 1200 mg/day or 2400 mg/day. During an eight-week baseline period, patients were required to have at least four seizures per month. Study drug was titrated during a two-week period, which was followed by a 24-week maintenance period.<br /> <br /> The median percent reduction from baseline in 28-day seizure frequency - the primary outcome measurement - was 26.4% for the 600 mg group, 40.2% for the 1200 mg group and 49.9% for the 2400 mg group, versus 7.6% for placebo (p=0.0001 for all doses).<br /> <br /> Over 65% of patients in the high-dose group discontinued treatment due to adverse events, the most common being vomiting, diplopia, ataxia, dizziness and nausea.</font> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times">Protocol 011</font></i></b> </p> </td> </tr> <tr> <td valign="top" width="21%"> </td> <td valign="top" width="79%"> <p> <font face="Helvetica Condensed" size="2">The double-blind pediatric adjunctive treatment study was conducted in 267 patients ages four to 17, who received one to two concomitant AEDs. After a 56-day baseline period, patients received placebo or OXC 900 mg/day (patients weighing 20-29 kg), 1200 mg/day (29.1-39 kg) or 1800 mg/day (&gt;39 kg). Doses were titrated over a 14-day period and patients then entered a 14-week maintenance phase.<br /> <br /> The study used the same primary outcome measure as protocol OT/PE1 and found that the median percent reduction in seizure frequency from baseline was 34.8% for OXC-treated patients versus 9.4% for placebo patients (p=0.0001).</font> </p> </td> </tr> </tbody> </table>